Molecular biomedicine最新文献

{"title":"Decoding the structure and translational promise of ROOL RNA nanocages.","authors":"Hanqi Lou, Yuemin Ding, Shiwei Duan","doi":"10.1186/s43556-025-00315-1","DOIUrl":"https://doi.org/10.1186/s43556-025-00315-1","url":null,"abstract":"","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"6 1","pages":"73"},"PeriodicalIF":10.1,"publicationDate":"2025-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Malate targets pyruvate kinase M2 to promote colorectal cancer cell cycle arrest and tumor suppression.","authors":"Kun Zhao, Fan Zhang, Qing Qin, Dapeng Zhang, Feng Yang, Yulan Huang, Renchao Deng, Huan Jing, Weidong Xiao, Hongming Miao, Rongchen Shi","doi":"10.1186/s43556-025-00326-y","DOIUrl":"https://doi.org/10.1186/s43556-025-00326-y","url":null,"abstract":"<p><p>To survive nutrient stress caused by rapid proliferation and dysfunctional vasculature, tumor cells extensively reprogram their metabolic pathways, including the tricarboxylic acid (TCA) cycle representing a critical remodeling node. Functioning as a key TCA cycle intermediate, malate bridges fumarate and oxaloacetate, both of which are metabolites known to play significant roles in tumorigenesis. However, whether malate itself regulates tumor progression and the specific mechanism remain unclear. In this study, we demonstrate that oral administration of malate significantly inhibits the growth of colorectal cancer (CRC) xenografts in both nude mice and immunocompetent models, suggesting its antitumor effects are immunity-independent. Mechanistically, we found that malate acts as an allosteric regulator of pyruvate kinase M2 (PKM2), binding to it and initiating a cascade that promotes the ubiquitin-mediated proteasomal degradation of cell division cycle 25 A (CDC25A). This reduction in CDC25A enhances the inhibitory phosphorylation of CDK1 at Tyr15, leading to cell cycle arrest and suppression of proliferation. Clinical analyses further support these findings, showing decreased malate levels in human CRC tissues. Moreover, the expression of malate-metabolizing enzymes, MDH1 and FH, is significantly correlated with activity of the CDC25A/p-CDK1 signaling axis. Collectively, our results identify malate as a non-metabolic regulator of the cell cycle, operating through the PKM2-CDC25A-CDK1 pathway, and propose a novel therapeutic strategy targeting metabolic mediators of cell proliferation in cancer.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"6 1","pages":"79"},"PeriodicalIF":10.1,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Healthy mitochondria attenuate metabolic dysfunction-associated steatohepatitis by restoring cell metabolism.","authors":"Peiyu Zhou, Jingli Li, Yafang Xie, Xiaorong Li, Zhihong Cui, Ailing Fu","doi":"10.1186/s43556-025-00328-w","DOIUrl":"https://doi.org/10.1186/s43556-025-00328-w","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatohepatitis (MASH) has become a major global health issue. Mitochondrial damage plays a crucial role in the development and progression of MASH. Therefore, it is speculated that mitochondrial transplantation therapy, which could replace dysfunctional mitochondria with normal ones, might potentially restore the liver cell metabolism of MASH. In palmitate-damaged AML-12 hepatocytes, exogenous mitochondria could eliminate lipid deposits and recover cell viability. However, in transforming growth factor β (TGF-β)-activated hepatic stellate cells (HSCs), the exogenous mitochondria showed the capability to inhibit the generation of α-smooth muscle actin (α-SMA) and collagen I. Moreover, the mechanism by which the exogenous mitochondria initiated the mitochondria-nucleus signaling pathway of liver cells was studied. The results showed the mitochondria could prevent metabolism disorders in the liver cells by regulating silent information regulator 1 (SIRT1) activity. Subsequently, a MASH animal model was established by the administration of a high-fat diet and the intraperitoneal injection of carbon tetrachloride to Kunming mice. The results indicated that the mitochondrial therapy significantly inhibited the livery injury and restored liver cell function in the experimental MASH mice (p < 0.01). The mitochondrial therapy would be a promising strategy to improve MASH pathological features, which could be developed as a new treatment option against MASH.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"6 1","pages":"80"},"PeriodicalIF":10.1,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"15-lipoxygenase blockade switches off pan-organ ischaemia-reperfusion injury by inhibiting pyroptosis.","authors":"Jie Li, Hailong Zhang, Mengmeng Dai, Yongpan Huang","doi":"10.1186/s43556-025-00325-z","DOIUrl":"10.1186/s43556-025-00325-z","url":null,"abstract":"<p><p>Even with reperfusion therapy, ischemia-reperfusion (I/R) injury remains to be a major driver of organ failure associated with myocardial infarction, stroke, and liver transplantation, with effective therapeutic targets still elusive. Using in vitro hypoxia/reoxygenation (H/R) models, we discovered that the pharmacological inhibition of 15-lipoxygenase (ALOX15) by thiolox effectively mitigates myocardial I/R injury. While ALOX15-a well-established promoter of lipid peroxidation and ferroptosis-has been extensively studied in cardiac I/R, its involvement in multi-organ I/R injury and non-ferroptotic cell death has not been thoroughly investigated. To address this, we employed I/R models in three vital organs and found that either global deletion of Alox15 or its specific loss in hematopoietic cells (Alox15^ΔH) consistently led to a reduction in infarct volume and improvement in function across the heart, brain, and liver. Mechanistically, this protection arose from the inhibition of pyroptosis. The underlying cascade involves mitochondrial reactive oxygen species (ROS) activating ALOX15 during reperfusion, which produces 15-HpETE, leading to a collapse of mitochondrial membrane potential (ΔΨm) and subsequent IP3R-mediated calcium (Ca²⁺) efflux. This Ca²⁺ surge initiates the assembly of NLRP3 inflammasome, driving GSDMD-dependent pyroptosis. Thus, ALOX15 acts as a keystone regulator bridging oxidative stress to pyroptosis via a mitochondria-Ca²⁺-pyroptosis axis. This axis functions independently of the organ type and is transmitted through both parenchymal and hematopoietic cells, suggesting that thiolox and targeted ALOX15 inhibition could be viable strategies for protecting multiple organs from I/R injury.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"6 1","pages":"77"},"PeriodicalIF":10.1,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12511505/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145260195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipin3 deficiency promotes hepatocyte ferroptosis and pyroptosis via activating JAK1-STAT3 pathway during acetaminophen induced acute liver injury.","authors":"Yu-Xing Liu, Qian Wang, Zi-Yu Xiangyang, Jie-Yi Long, Hao Huang, Liang-Liang Fan","doi":"10.1186/s43556-025-00317-z","DOIUrl":"https://doi.org/10.1186/s43556-025-00317-z","url":null,"abstract":"<p><p>Lipin3 belongs to the Lipin protein family and is pivotal in modulating lipid homeostasis, inflammatory signaling, and lineage commitment. However, research on Lipin3 is limited, and its role in liver diseases remains poorly defined. This study investigated the function of Lipin3 in acetaminophen (APAP)-induced acute liver injury (ALI). Lipin3 expression was analyzed in public ALI datasets, ALI patients, APAP-challenged mouse models and primary hepatocytes. Lpin3-knockout (Lpin3-KO) mice and adeno-associated virus (AAV)-overexpressing Lpin3 mice were generated to assess the pathophysiological role of Lipin3. Mechanistic studies, including mass spectrometry, coimmunoprecipitation, and bioinformatics prediction, were conducted in primary hepatocytes and HepG2 cells. Our key findings were as follows: Lipin3 levels were markedly reduced in ALI patients, APAP-treated mice, and hepatocytes. Compared with wild-type mice, Lpin3-KO mice exhibited exacerbated ALI severity after post-APAP exposure. Lipin3 deficiency promoted hepatocyte ferroptosis (via lipid peroxidation/ACSL4) and pyroptosis (via GSDME cleavage). Mechanistically, Lipin3 directly interacts with JAK1 to suppress its phosphorylation, thereby inhibiting STAT3-driven activation of ACSL4 (ferroptosis) and GSDME (pyroptosis). Lipin3 overexpression mitigated APAP-induced hepatocyte ferroptosis and pyroptosis, thereby alleviating ALI. Our results demonstrate that Lipin3 depletion aggravates ALI through the dual regulation of ferroptosis and pyroptosis through the JAK1-STAT3 axis, suggesting that Lipin3 is a potential therapeutic target for APAP-induced liver injury.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"6 1","pages":"78"},"PeriodicalIF":10.1,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145276853","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Moyamoya disease: epidemiology, clinical features, pathogenesis, diagnosis and therapeutic interventions.","authors":"Xinyue Cheng, Ying Cao, Junbo Duan, Min Zhou, Shoudong Ye, Yuqing Zhu","doi":"10.1186/s43556-025-00318-y","DOIUrl":"10.1186/s43556-025-00318-y","url":null,"abstract":"<p><p>Moyamoya disease (MMD) is a rare cerebrovascular disorder characterized by progressive stenosis of the intracranial internal carotid arteries and the development of compensatory, fragile collateral vascular networks at the skull. Emerging evidence suggests that the pathogenesis of MMD involves genetic/epigenetic predisposition, dysregulated immune responses, and environmental triggers. Notably, the RNF213 p.R4810K variant has been identified as a key genetic susceptibility factor, particularly in East Asian populations. However, the molecular mechanisms underlying disease progression remain incompletely elucidated, primarily due to the limited availability of patient-derived cerebrovascular tissues and the lack of animal models that faithfully recapitulate the full spectrum of human MMD pathology. These constraints have impeded the development of targeted therapeutic interventions. Diagnostically, digital subtraction angiography (DSA) continues to serve as the gold standard for diagnosing MMD, enabling detailed visualization of steno-occlusive lesions and characteristic moyamoya vessels. Current clinical management relies predominantly on surgical revascularization to enhance cerebral perfusion, yet this strategy does not alter the fundamental disease process. Recent advances in patient-derived vascular organoids and serum-stimulated cellular models have facilitated drug screening and biomarker identification. In this review, we provide a systematic overview of the epidemiology, clinical manifestations, and genetic landscape of MMD, with a focus on recent progress in deciphering its molecular basis. We further discuss the transformative potential of induced pluripotent stem cell (iPSC) technology, particularly when combined with CRISPR-based gene editing, for modeling MMD vasculopathy, investigating the functional impact of RNF213 mutations, and exploring precision repair approaches. These innovative approaches offer novel insights into disease mechanisms and open new avenues for therapeutic intervention in MMD.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"6 1","pages":"76"},"PeriodicalIF":10.1,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12511514/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145260280","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cholesterol metabolism: molecular mechanisms, biological functions, diseases, and therapeutic targets.","authors":"Daxin Cui, Xiaoqian Yu, Qiuyue Guan, Ying Shen, Jiajing Liao, Yin Liu, Zhiguang Su","doi":"10.1186/s43556-025-00321-3","DOIUrl":"10.1186/s43556-025-00321-3","url":null,"abstract":"<p><p>Cholesterol, an indispensable structural and signaling lipid, is fundamental to cellular membrane integrity, steroidogenesis, and developmental morphogen pathways. Its homeostasis hinges on the precise coordination of four interdependent metabolic modules: de novo biosynthesis, intestinal absorption, enzymatic conversion, and systemic clearance. This review delineates the molecular machinery governing these processes-from the Bloch/Kandutsch-Russell synthesis pathways and niemann-pick C1-like 1 (NPC1L1)-mediated cholesterol uptake to cholesterol 7α-hydroxylase (CYP7A1)-driven bile acid synthesis and HDL-dependent reverse transport. We further elucidate cholesterol's multifaceted roles in lipid raft assembly, Hedgehog signal transduction, and vitamin D/hormone production. Critically, dysregulation of cholesterol flux underpins pathogenesis in atherosclerosis, metabolic dysfunction-associated fatty liver disease (MAFLD), neurodegenerative disorders, and oncogenesis, with disrupted synthesis, efflux, or esterification cascades serving as key drivers. Emerging therapeutic strategies extend beyond conventional statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors to include transformative modalities: CRISPR-based in vivo gene editing (e.g., VERVE-101 targeting PCSK9), small interfering RNA (siRNA) therapeutics (inclisiran), and microbiota-directed interventions. Pioneering approaches against targets Such as angiopoietin-like 3 (ANGPTL3), lipoprotein(a) [Lp(a)], and asialoglycoprotein receptor 1 (ASGR1)-alongside repurposed natural agents (berberine, probiotics)-offer promise for mitigating residual cardiovascular risk and advancing precision cardiometabolic medicine. By integrating mechanistic insights with clinical advancements, this review underscores the transition from broad-spectrum therapies to personalized, multi-target regimens, offering a roadmap for mitigating cholesterol-related diseases in the era of genomic and metabolic medicine.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"6 1","pages":"72"},"PeriodicalIF":10.1,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12508344/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145253834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Atopic dermatitis: diagnosis, molecular pathogenesis, and therapeutics.","authors":"Ruimin Bai, Yan Zheng, Xiaofeng Dai","doi":"10.1186/s43556-025-00313-3","DOIUrl":"10.1186/s43556-025-00313-3","url":null,"abstract":"<p><p>Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by acute and chronic phases with no definitive cure currently available. The diagnosis of AD involves the evaluation of both disease onset and severity, relying on established clinical criteria and, increasingly, on various biomarkers to improve diagnostic accuracy. The molecular pathogenesis of AD is driven by a combination of genetic predispositions, environmental factors, and immune dysregulation. Acute AD is predominantly mediated by T-helper cell 2 (Th2) immune responses, whereas chronic AD involves a shift toward Th1-driven inflammation. Within this immunological context, we emphasize the role of redox imbalance in disease progression and propose a wound-healing model to explain the molecular dynamics of AD. According to this model, the acute phase is marked by excessive oxidative stress, requiring antioxidant intervention, whereas the chronic phase is characterized by insufficient redox signaling, which hinders the clearance of hyperproliferative cells. We further review current and emerging therapeutic strategies, including anti- and pro-oxidative strategies, based on the different AD staging. Notably, we introduced cold atmospheric plasma (CAP), a redox regulatory tool, as a novel treatment modality for AD management that stimulates antioxidant responses at low to moderate doses and induces oxidative stress at higher concentrations, potentially reversing chronic AD pathology. This review offers a comprehensive overview of AD, from clinical manifestations and molecular pathogenesis to therapeutic approaches, and introduces the 'wound healing model' as a conceptual framework to integrate CAP as an innovative treatment modality for AD management and to inform future research.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"6 1","pages":"71"},"PeriodicalIF":10.1,"publicationDate":"2025-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12497682/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145234463","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Adipose-Derived Stem Cell Therapy Attenuates HIF-1α/mTOR/REDD1 Signaling in Obese Hypertensive Rats.","authors":"Renata Nakamichi, Mario Luis Ribeiro Cesaretti, Eric Rafael Andrade Silva, Camila Nunes Oliveira, Evelyn Manuella Martins Gomes Jodas, Miguel Cendoroglo Neto, Beata Marie Redublo Quinto, Marcelo Costa Batista","doi":"10.1186/s43556-025-00288-1","DOIUrl":"10.1186/s43556-025-00288-1","url":null,"abstract":"","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"6 1","pages":"70"},"PeriodicalIF":10.1,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12491122/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145214574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Iron accumulation in hypothalamus promotes age-dependent obesity and metabolic dysfunction of male mice.","authors":"Xinyu Wang, Xiaoyue Xiong, Ye Xuan, Wen Tian, Liwei Chen, Zhuo Chen, Yi Zhang, Wei L Shen, Cheng Hu","doi":"10.1186/s43556-025-00324-0","DOIUrl":"10.1186/s43556-025-00324-0","url":null,"abstract":"<p><p>With the progression of aging, age-dependent obesity and metabolic disorders have garnered increasing attention, yet their underlying mechanisms remain poorly understood. Dysregulation of iron homeostasis is strongly linked to aging; however, its role in age-dependent obesity remains unclear. As the hypothalamus, a key regulator of energy homeostasis, plays a pivotal role in metabolic regulation during aging, we investigated whether hypothalamic iron accumulation contributes to age-dependent obesity. We first observed elevated iron levels in the hypothalamus of aged mice, particularly in the arcuate nucleus. To test whether reducing iron could mitigate obesity, we intranasally administered the iron chelator deferiprone to aged mice and found that it effectively lowered hypothalamic iron levels and ameliorated metabolic function. Using a ferric ammonium citrate-induced iron overload cell model, we discovered that excess iron triggers mitochondrial dysfunction and oxidative stress, leading to ROS-dependent nuclear translocation of forkhead box protein O1 (FoxO1) and subsequent upregulation of AgRP expression. To confirm this mechanism in vivo, we generated agouti-related peptide (AgRP) neuron-specific transferrin receptor 1(Tfrc) knockout mice and found that reducing iron uptake in these neurons decreased ROS levels, inhibited FoxO1 nuclear translocation, and suppressed AgRP neuronal activity in aged mice. This intervention ultimately protected against age-related obesity and metabolic dysfunction. Our study identifies a critical iron accumulation-ROS-FoxO1-AgRP signaling axis in hypothalamic neurons as a key driver of age-dependent obesity. This study elucidates the broader implications of iron homeostasis dysregulation in aging-associated pathologies and offers novel perspectives for investigating age-dependent obesity.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"6 1","pages":"75"},"PeriodicalIF":10.1,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12491144/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145208345","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}